The invention relates to a process for the preparation of chiral xcex1-hydroxycarboxylic acids, which are valuable intermediates for pharmaceutical and agrochemical products, from C4-C6-ketones.
xcex1-Hydroxycarboxylic acids, such as, for example, 2-hydroxy-2-methyl-3-phenylthiopropionic acid, are employed, for example according to EP 0 100 172, in the preparation of acylanilides, which have anti-androgenic activity. According to EP 0 100 172, these xcex1-hydroxy-carboxylic acids are obtained as a racemate by reaction of the appropriate phenylthioketones with KCN to give the corresponding cyanohydrin and subsequent reaction with aqueous HCl. Yields, purities, and details of the configuration can be taken from EP 0 100 172.
Phenylthioketones which can serve as a precursor for the above reaction, such as, for example, 4-phenylthio-2-butanone, are obtained, for example according to J. Org. Chem. 1995, 60, 2022-2025, by addition of thiophenol to methyl vinyl ketone.
According to J. Org. Chem. 1990, 55, 4643-4647, racemic tert-xcex1-benzyloxy acid esters are in each case cleaved into the corresponding (+)-tert-xcex1-benzyloxy acid ester and the corresponding (S)-xcex1-benzyloxycarboxylic acid by means of lipase OF from Candida cylindracea. The desired chiral xcex1-hydroxycarboxylic acids, such as, for example, (S)-2-hydroxy-2-methyl-butyric acid, are then obtained from the (S)-xcex1-benzyloxycarboxylic acids by hydrogenation. The yield in this process is 67%. The ee value of the final product is only 60%.
The object of the present invention was to find a process for the preparation of short-chain C4-C6-xcex1-hydroxycarboxylic acids which makes possible the preparation of the desired products in high yield and enantiomeric purity.
Unexpectedly, it was possible to achieve this object by means of a process in which low-molecular-weight C4-C6-ketones derivatized with a chemically removable group are converted into the corresponding xcex1-hydroxycarboxylic acids by reaction with a cyanide group donor in the presence of a hydroxynitrile lyase or by racemic reaction, subsequent acidic hydrolysis, optionally resolution, and cleavage of the group.
The invention accordingly relates to a process for the preparation of chiral xcex1-hydroxycarboxylic acids of the formula (I) 
in which R1 is a C1-C2-alkyl radical optionally substituted by one or more halogen atoms and R2 is a C2-C3-alkyl radical optionally substituted by one or more halogen atoms, which comprises reacting a compound of the formula (II), 
in which R1 is as defined above, R2xe2x80x2 is a C2-C3-alkylene radical optionally substituted by one or more halogen atoms, m can be equal to 0 or 1, R is a C1-C20-alkyl radical, a C5-C20-aryl radical, heteroaryl radical or a heterocyclyl radical, where the radicals can optionally be mono- or polysubstituted by substituents from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C1-C6-alkylthio, phenyl, benzyl, halogen, hydroxyl, nitro, carboxyl, esters, thioesters, carbonates, carbamates or urethanes, and X can be oxygen, sulfur, sulfinyl, sulfonyl, imino, C1-C6-alkylimino, xanthate, silyl, or, if m is equal to 0, halogen,
in the presence of a cyanide group donor either enantioselectively with an (R)- or (S)-hydroxynitrile lyase in an organic, aqueous or 2-phase system or in emulsion to give the corresponding (R)- or (S)-cyanohydrin of the formula (III) 
in which R1, R2xe2x80x2, R, m and X are as defined above, or racemically to give the corresponding racemate of the cyanohydrin of the formula (III), then converting the compound of the formula (III) or its racemate by means of acidic hydrolysis into the corresponding acid of the formula (IV) 
in which R1, R2xe2x80x2, R, m and X are as defined above, or its racemate, whereupon the elimination of the group of the formula (V)
(R)m-Xxe2x80x83xe2x80x83(V)
takes place, where in the case of the racemate a resolution is first carried out, and isolating the desired chiral xcex1-hydroxycarboxylic acid of the formula (I).
In the process according to the invention, chiral xcex1-hydroxycarboxylic acids of the formula (I) 
are prepared.
In the formula (I), R1 is a C1-C2-alkyl radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, methyl, ethyl, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, etc. A methyl radical optionally substituted by one to 3 fluorine or chlorine atoms is preferred, and an unsubstituted methyl radical is particularly preferred.
R2 is a C2-C3-alkyl radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, ethyl, difluoroethyl, propyl, pentafluoroethyl, etc. Preferably, R2 is an ethyl radical optionally substituted by one or more fluorine or chlorine atoms, particularly preferably an unsubstituted ethyl radical.
Preferably, in the compounds of the formula (I) R2 has one C atom more than R1.
Examples of compounds of the formula (I) are (R)- or (S)-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-2-hydroxy-2-ethylpentanoic acid, (R)- or (S)-2-hydroxy-2-fluoromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-chloromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-difluoromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-dichloromethylbutanoic acid, (R)- or (S)-2-hydroxy-2-trifluoromethylbutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-methylbutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-fluoromethylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-fluoro-methylbutanoic acid, (R)- or (S)-3-difluoro-2-difluoromethyl-2-hydroxy-butanoic acid, (R)- or (S)-4-difluoro-2-difluoromethyl-2-hydroxybutanoic acid, (R)- or (S)-3-difluoro-2-hydroxy-2-trifluoromethylbutanoic acid, (R)- or (S)-4-difluoro-2-hydroxy-2-trifluoromethylbutanoic acid, (2S,3S)-3-fluoro-2-hydroxy-2-methylbutanoic acid, (2S,3R)-3-fluoro-2-hydroxy-2-methyl-butanoic acid, (2R,3S)-3-fluoro-2-hydroxy-2-methylbutanoic acid, (2R,3R)-3-fluoro-2-hydroxy-2-methylbutanoic acid, etc.
The starting material used is the compound of the formula (II) 
In the formula (II), R1 is as defined above.
R2xe2x80x2 is a C2-C3-alkylene radical optionally substituted by one or more halogen atoms from the group consisting of fluorine, chlorine, bromine, iodine, such as, for example, ethylene, propylene, difluoroethylene, pentafluoroethylene, dichloroethylene, pentachloroethylene etc. Preferably, R2xe2x80x2 is an ethylene radical optionally substituted by one or more fluorine or chlorine atoms, particularly preferably an unsubstituted ethylene radical.
m can be equal to 0 or 1 and R is a C1-C20-alkyl radical, a C5-C20-aryl radical, heteroaryl radical or a heterocyclyl radical.
Alkyl in this case is to be understood as meaning saturated or mono- or polyunsaturated, linear, branched or cyclic, primary, secondary or tertiary hydrocarbon radicals. These are C1-C20-alkyl radicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, octyl, cyclo-octyl, decyl, cyclodecyl, dodecyl, cyclododecyl etc.
C1-C12-alkyl radicals and particularly preferably C2-C8-alkyl radicals are preferred here.
The alkyl group can optionally be mono- or polysubstituted by substituents which are inert under the reaction conditions, from the group consisting of C1-C4-alkoxy, C1-C6-alkylthio, phenyl, benzyl, halogen, hydroxyl, nitro, carboxyl, esters, thioesters, carbonates, carbamates or urethanes.
Aryl is preferably to be understood as meaning C6-C20-aryl groups, such as, for example, phenyl, biphenyl, naphthyl, indenyl, fluorenyl etc.
The aryl group can in this case be optionally mono- or polysubstituted by substituents which are inert under the reaction conditions, from the group consisting of C1-C4-alkyl, C1-C4-alkoxy, C1-C6-alkylthio, phenyl, benzyl, halogen, hydroxyl, nitro, carboxyl, esters, thioesters, carbonates, carbamates or urethanes.
Heteroaryl or heterocyclyl are to be understood as meaning cyclic radicals which contain at least one S, O or N atom in the ring. These are, for example, furyl, thienyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiazolyl, quinolyl, isoquinolyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, isoxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, phthalazinyl etc.
Functional O or N groups can in this case be protected if necessary. The heteroaryl group or the heterocycle can in this case be optionally mono- or polysubstituted by the substituents already mentioned above.
Preferably, m is equal to 1 and R is a C5-C20-aryl or heteroaryl radical, such as phenyl, naphthyl, pyridyl, pyrimidinyl, benzothiazolyl, which can optionally be mono- or disubstituted by methyl, fluorine, chlorine, hydroxyl or nitro.
Particularly preferably, R is phenyl.
X in the compound of the formula (II) can be boron, oxygen, sulfur, sulfinyl (xe2x80x94SOxe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), imino (xe2x80x94NHxe2x80x94), C1-C6-alkylimino, xanthate (xe2x80x94Oxe2x80x94CSxe2x80x94Sxe2x80x94), silyl (xe2x80x94Sixe2x80x94), or, if m is equal to 0, halogen.
Preferably, X is sulfur, sulfinyl (xe2x80x94SOxe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), xanthate (xe2x80x94Oxe2x80x94CSxe2x80x94Sxe2x80x94) or silyl (xe2x80x94Sixe2x80x94).
Suitable starting compounds are, for example, 4-phenylthio-2-butanone, 4-phenylthio-4-difluoro-2-butanone, 4-phenylthio-3-difluoro-2-butanone, 4-phenylthio-1-fluoro-2-butanone, 4-phenylthio-1-difluoro-2-butanone, 4-phenylthio-1-trifluoro-2-butanone, 4-trimethylsilyl-2-butanone, 4-dimethylphenylsilyl-2-butanone, 4-diphenylmethylsilyl-2-butanone, 4-triphenylsilyl-butanone, 4-(9-borabicyclo[3.3.1]nonan-9-yl)-2-butanone, 4-diphenyl-borane-2-butanone, 4-benzylimino-2-butanone, 4-phenylsulfinyl-2-butanone, 4-phenylsulfonyl-2-butanone, O-(1-methylethyl) S-(3-oxybutyl) dithiocarbonate, O-(phenyl)-S-(3-oxybutyl) dithiocarbonate, etc.
The compounds of the formula (II) can be prepared from the corresponding ketones, for example analogously to J. Org. Chem. 1995, 60, 2022-2025, Khim. Tekhnol. (1980), 23(7), 836f. or analogously to Zhur. Org. Khim., 1971, 7, 2221. Compounds of the formula (II) in which X is sulfinyl or sulfonyl can also be prepared, for example, by oxidation of the corresponding compound of the formula (I) in which X is sulfur.
Preferably, the compounds of the formula (II) are prepared according to a slightly modified variant of J. Org. Chem. 1995, 60, 2022-2025.
Thus, for example, 4-phenylthio-2-butanone is prepared by reaction of thiophenol with methyl vinyl ketone in the presence of a tertiary amine, for example triethylamine, as a catalyst in a suitable solvent, such as, for example, methyl tert-butyl ether (MTBE) at 0xc2x0 C.-10xc2x0 C. and 4-phenylthio-2-butanone is isolated by extraction.
If, in the next step, the reaction with a cyanide group donor, the same solvent, for example MTBE, is employed, the compound of the formula (II) does not have to be completely isolated; the organic phase which contains the compound of the formula (II) can be employed directly. If, in these two steps, a different solvent is employed, it may be necessary to carry out a solvent exchange.
Preferably, in the preparation of the compound of the formula (II) the same solvent is used as in the following reaction with the cyanide group donor.
The compound of the formula (II) is then reacted with a cyanide group donor, it being possible for the reaction to be carried out enantioselectively in the presence of an (R)- or (S)-hydroxynitrile lyase (HNL) or in a racemic, base-catalyzed way, for example using Amberlyst, triethylamine, diazabicyclooctane, pyridine or another organic base. A suitable cyanide group donor is hydrocyanic acid, alkali metal cyanides or a cyanohydrin of the general formula (VI)
R3R4C(OH)(CN).
In the formula (VI), R3 and R4 independently of one another are hydrogen or an unsubstituted hydrocarbon group, or R3 and R4 together are an alkylene group having 4 or 5 C atoms, where R3 and R4 are not simultaneously hydrogen. The hydrocarbon groups are aliphatic or aromatic groups, preferably aliphatic groups. Preferably, R3 and R4 are alkyl groups having 1-6 C atoms; acetone cyanohydrin as the cyanide group donor of the formula (VI) is very preferred.
The cyanide group donor can be prepared according to known processes. Cyanohydrins, in particular acetone cyanohydrin, can also be purchased. Preferably, hydrocyanic acid (HCN), KCN, NaCN or acetone cyanohydrin, particularly preferably hydrocyanic acid, is employed as the cyanide group donor.
The hydrocyanic acid can in this case also be released from one of its salts such as, for example, NaCN or KCN, only shortly before the reaction and added to the reaction mixture as such or in dissolved form.
The cyanide group donor is in this case employed in a molar ratio to the compound of the formula (II) of 0.5:1 to 5:1, preferably of 0.8:1 to 4:1 and particularly preferably of 1:1 to 3:1.
The reaction can be carried out in an organic, aqueous or 2-phase system or in emulsion.
Organic diluents used can be aliphatic or aromatic hydrocarbons which are immiscible or slightly miscible with water and which are optionally halogenated, alcohols, ethers or esters or mixtures thereof. Preferably, methyl tert-butyl ether (MTBE), diisopropyl ether, dibutyl ether and ethyl acetate or a mixture thereof are employed.
In the enantioselective reaction, the aqueous system used is an aqueous solution or buffer solution containing the corresponding HNL. Examples thereof are Na citrate buffer, phosphate buffer etc.
The HNLs can be present in the organic diluent here either as such or immobilized, but the reaction can also be carried out in a two-phase system or in emulsion with nonimmobilized HNL.
Suitable HNLs are both native and recombinant (R)- and (S)-HNLs, such as are known from the prior art, for example from EP 0 969 095, EP 0 951 561, EP 0 927 766, EP 0 632 130, EP 0 547 655, EP 0 326 063, WO 01/44487 etc.
The base- or enzyme-catalyzed addition of the cyanide group to the appropriate compound of the formula (II) can in this case be carried out analogously to the prior art, for example analogously to EP 0 969 095, EP 0 951 561, EP 0 927 766, EP 0 632 130, EP 0 547 655, EP 0 326 063 etc.
The corresponding (R)- or (S)-cyanohydrin of the formula (III) or its racemate can then be hydrolyzed without further purification analogously to the prior art, for example as described in Angew. Chem. 1994, 106, p.1615 or in Tetrahedron Letters, Vol. 31, No. 9, pp 1249-1252, 1990, using concentrated hydrochloric acid, for example after extraction or, if appropriate, after filtering off the enzyme and distilling off the solvent. Other suitable acids, such as, for example, H2SO4, can also be used for the hydrolysis, but HCl is preferably employed.
The working up of the reaction solution, which contains the crude (R)- or (S)-xcex1-hydroxycarboxylic acids which are obtained in this way and have approximately the same optical purity as the corresponding (R)- and (S)-cyanohydrins, can then be carried out either directly or after dilution of the resulting reaction solution with water and subsequent extraction with MTBE, toluene, xylene, (poly)ethers, halogenated hydrocarbons, acetonitrile etc. between 10-99xc2x0 C., preferably between 15-95xc2x0 C. and particularly preferably between 20-90xc2x0 C. Preferably, toluene or xylene is used here.
To achieve an enrichment of the desired enantiomer, the extraction solution is preferably concentrated and strongly cooled down to xe2x88x9210xc2x0 C. After this, the resulting crystals are separated off, for example by means of a suction filter, recrystallized, preferably in an aromatic hydrocarbon, if appropriate in the presence of a cosolvent and the product is obtained with a higher ee than in the cyanohydrin stage.
Further, it is possible to couple the crystallization step directly to the hydrolysis step so that the extraction of the hydroxycarboxylic acid by means of ethers is unnecessary. To this end, an aromatic hydrocarbon, if appropriate in combination with a cosolvent, is added to the hydrolysis solution at hydrolysis temperature and the reaction mixture is extracted. The aqueous phases are discarded, whereupon the combined organic phases are cooled, preferably after concentration, and the highly pure hydroxycarboxylic acids crystallize out.
If the racemate of the xcex1-hydroxycarboxylic acid (IV) is obtained, resolution with a cleavage base is first carried out. Suitable cleavage bases are, for example, chiral amines, for example those such as are described, for example, in T. Vries et al., Angew. Chem., Int. Ed., (1998), 37, pp 2349-2354, such as, for example, (R)- or (S)-phenylethylamine, (L)- or (D)-phenylglycinamide, (L)- or (D)-norephedrine, (R)- or (S)-naphthylethylamine etc.
The cleavage is carried out in a solvent in which the xcex1-hydroxycarboxylic acid dissolves, for example in isopropyl acetate (IPA), ethyl acetate, toluene, xylene. After the addition of the cleavage base, crystallization is begun by cooling the reaction mixture with stirring. In the crystallization, it is also possible to assist or induce this by seeding. Cooling down to xe2x88x9215xc2x0 C. is carried out, preferably down to approximately +10xc2x0 C. After crystallization is complete, the mixture is filtered, and the crystals are optionally washed and optionally then dried.
To release the corresponding chiral acid, HCl is then added to a mixture of chiral salt, water and a suitable solvent, whereby two clear phases are obtained. Suitable solvents are those which are immiscible with water, which dissolve the acid and which are resistant to HCl. Examples thereof are ethers and hydrocarbons. Preferably, ethers are employed, particularly preferably MTBE.
If the corresponding enantiomerically enriched xcex1-hydroxycarboxylic acid is then present in purified form, the cleavage of the chemically removable group of the formula (V) is carried out.
This is carried out, for example, in the case where Xxe2x95x90S and derivatives thereof by means of Raney Ni, NiCl2 and NaBH4, Cl2, resulting halides having to be removed, for example, by means of zinc, such as, for example, analogously to J. Org. Chem., Vol. 58, No. 9, 1993, 2407-2413. If Xxe2x95x90O, the group RmO can be removed by elimination, an unsaturated xcex1-hydroxycarboxylic acid in this case being formed by elimination, which optionally has to be hydrogenated.
If Xxe2x95x90Si, the group RmSi can be removed by basic work-up (K2CO3 in methanol), by treatment with fluoride ions (KF, NaF) or conc. HCl for a number of hours.
By means of the process according to the invention, chiral xcex1-hydroxycarboxylic acids are obtained from C4-C6-ketones in high yields and in high enantiomeric purity, it being possible for the enantioselective HCN addition to proceed significantly more selectively than according to the prior art and for the resolution after the racemic HCN addition needing to be carried out using simpler resolving reagents than according to the prior art.